British patent GB-B 774,064 is concerned with a process for the production of 15-substituted testosterone, particularly 15-hydroxytestosterone. Therapeutic applications of these substances are nowhere mentioned in the patent.
French patent application FR-A 2 035 786 describes veterinary applications of 16α-α-D-glucosiden of 16α,17-dihydroxysteroids. It is stated that these steroids can be used as estrogens to prevent ovulation in animals such as rodents, dogs, cow and sheep. Claim 3 mentions the glucoside of 16α-hydroxytestosterone. Only parenteral administration is mentioned in the French application.
At present, the main therapeutic application of androgenic steroids is in the treatment of hypogonadal males. Methods of treating androgen deficiency comprising the administration of androgens, such as testosterone, dihydrotestosterone, dehydroepiandrosterone and various esters of testosterone, or derivatives and analogues such as mesterolone are known in the art.
Three types of androgen deficiency in males are usually distinguished, i.e. primary androgen deficiency (testicular insufficiency), secondary androgen deficiency (hypothalamo-hypophyseal insufficiency) and androgen deficiency in ageing males (ADAM), also known as “male menopause” or “andropause”.
As regards the long-term administration of androgens to males, a distinction can be made between therapy and supplementation. Therapy typically requires relatively high doses that are usually similar to the rate of production of endogenous androgens. Supplementation on the other hand is suitably done with dosages that are below the rate of production of endogenous androgens (i.e. testosterone, dihydrotestosterone and dehydroepiandrosterone).
Because of concerns about undesirable side effects, androgens are only used sparingly in both therapy and hormone supplementation. Indeed, androgens are normally only used for therapy in human males when primary or secondary androgen deficiency has been diagnosed.
Only a few androgens, e.g. dehydroepiandrosterone (DHEA) and 17α-alkylated derivatives of testosterone, are suitable for oral administration because, unlike testosterone, they are largely resistant to hepatic metabolism. However, disadvantages of oral to administration are associated with the bad absorption of these androgens and the relatively high effect they exert on the liver and particular the liver metabolism (Bhasin et al. (1997) J. Clin. Endocr. Metab. 82:3-8). This is why, in existing protocols, androgens are generally administered in the form of 2-3 weekly depot injections or implants.
It has also been suggested in the prior art to use a combination of a progestogen and an androgen in a method of male contraception. In such a method the progestogen is administered in a sufficiently high amount to halt spermatogenesis—leading to azoospermia—and the androgen is co-administered to prevent androgen deficiency which would otherwise result from the administration of the progestogen. Because of concerns about reliability and possible side-effects of the androgenic component, particularly when administered orally, male contraceptive have not yet made it beyond the experimental stage.
Other therapeutic uses of androgens that have been proposed in the prior art include treatment of the wasting syndrome and retro-viral drug induced lipodystrophia in HIV infected individuals, enhancement of recovery of critically ill catabolic individuals, treatment of benign gynaecological disorders hormonal contraception in females, delayed puberty, female-to-male conversion.
As will be apparent from the above, there is an unmet need for androgens that (i) can be used effectively in the above mentioned therapeutic methods without causing undesirable side-effects, (ii) produce a very consistent, i.e. predictable, impact and/or (iii) may be administered in a convenient manner, especially orally.